Project Summary/Abstract Despite the universal use and success of combination antiretroviral therapy (CART), more than 30% of people living with human immunodeficiency virus infection (PLWHIV) in the US are suffering from depression. Although accumulating evidence suggests that sustained systemic and CNS inflammation are commonly observed in patients with major depressive disorder and PLWHIV, the pathophysiology underlying depression among PLWHIV remain poorly investigated. In this K01 proposal, the candidate hypothesizes that there is a crosstalk between the gut bacterial and fungal communities, which if disrupted, may lead to sustained inflammation and depressive-like phenotypes in the EcoHIV mouse model. The candidate also hypothesizes that pachyman, a natural product of 1,3-D-?-glucan, can rescue the EcoHIV-induced depressive-like behaviors, gut bacterial-fungal dysbiosis, and sustained inflammation, based on the preliminary results showing that pachyman has an antidepressant effect which is dependent on inhibition of Dectin-1, a pattern- recognition ?-D-Glucan receptor. To test the hypothesis, three specific aims are proposed: (1) To identify and phenotypically characterize the nature of HIV-induced depressive-like behaviors in the EcoHIV mouse model. (2) To identify and study HIV-induced alterations in gut microbiota in conjunction with inflammatory signaling in the gut, circulation and in the central nervous system. (3) To determine whether pachyman treatment ameliorates HIV-induced depressive-like behaviors, and modulates gut microbiota and inflammatory signaling via dectin-1 inhibition. To achieve the 3 specific aims, 4 short-time training steps/goals are required: (i) To become proficient at the study of social behavior phenotypes and immune characteristics of HIV mice models-- the candidate will be mentored by Drs. Atsushi Kamiya, Barbara Slusher, and Amanda Brown, with Consultancy/collaboration with Drs. David Volsky and Norman Haughey. Training will occur at Johns Hopkins. (ii) To successfully conduct 16S and ITS2 targeted Metagenomic sequencing profiling, perform accurate biostatics analyses, and correctly interpret and synthesize biological meaning from gut microbiota datasets--the candidate will be trained by Drs. Robert Yolken and Sarah Wheelan at Johns Hopkins. (iii) To receive basic science hands-on training as well as didactic training in the pharmacology of natural products and drug development by Dr. Slusher. (iv) To receive knowledge and skills training in epidemiology, clinical manifestations, biomarkers selection, translational therapeutics, and research methodology for depression in PLWHIV by Dr. Justin McArthur. Above all, the long-term goal of this K01 proposal is to develop an independent research laboratory equipped to independently study the treatment effects of natural products on gut bacterial-fungal dysbiosis-induced inflammatory mechanisms in HIV-associated neuropsychiatric disorders, and to develop a programmatic line of research by successfully competing for funding.